title: Secretoneurin gene therapy improves blood flow in an ischemia model in type 1 diabetic mice by enhancing therapeutic neovascularization.
abstract: Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed. These results were complemented by the clinical observation of reduced necrosis and by an increased number of capillaries and arterioles in the SN-treated animal group. In vitro, we found that SN is capable of promoting proliferation and chemotaxis and reduces apoptosis in HUVECs cultured under hyperglycemic conditions. Additionally, SN activated ERK, eNOS and especially AKT as well as EGF-receptor in hyperglycemic HUVECs. In conclusion, we show that SN gene therapy improves post-ischemic neovascularization in diabetic mice through stimulation of angiogenesis and arteriogenesis indicating a possible therapeutic role of this factor in ischemia-related diseases in diabetic patients.
authors.affiliation: Internal Medicine III (Cardiology and Angiology), Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schgoer
authors.forename: Markus
authors.initials: M
authors.lastname: Theurl
authors.forename: Karin
authors.initials: K
authors.lastname: Albrecht-Schgoer
authors.forename: Verena
authors.initials: V
authors.lastname: Jonach
authors.forename: Bernhard
authors.initials: B
authors.lastname: Koller
authors.forename: Daniela
authors.initials: D
authors.lastname: Lener
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Franz
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D004730:Endothelium, Vascular / Q000166:cytology; D015316:Genetic Therapy; D006801:Humans; D007511:Ischemia / Q000150:complications / Q000628:therapy; D051379:Mice; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000235:genetics*; D012039:Regional Blood Flow; D053381:Secretogranin II / Q000235:genetics*; D013311:Streptozocin
chemical_list: D009479:Neuropeptides; D053381:Secretogranin II; C081159:secretoneurin; D013311:Streptozocin